chrX-54440775-G-T

Variant names:

• chrX-54440775-G-T
• rs140822042
• NM_058163.3:c.167G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_058163.3(TSR2):​c.167G>T​(p.Arg56Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000465 in 1,075,545 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: TSR2 NM_058163.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222
• Publications: 0 publications found

Genes affected

TSR2 (HGNC:25455): (TSR2 ribosome maturation factor) The protein encoded by this gene appears to repress the transcription of NF-kappaB and may be involved in apoptosis. Defects in this gene are a cause of Diamond-Blackfan anemia. [provided by RefSeq, Oct 2016]

TSR2 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Diamond-Blackfan anemia 14 with mandibulofacial dysostosis

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13814986).
• BS2: High AC in GnomAdExome4 at 5 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058163.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR2	NM_058163.3	MANE Select	c.167G>T	p.Arg56Leu	missense	Exon 2 of 5	NP_477511.1	Q969E8
	TSR2	NM_001346789.2		c.167G>T	p.Arg56Leu	missense	Exon 2 of 5	NP_001333718.1
	TSR2	NM_001346790.2		c.-221G>T		5_prime_UTR	Exon 2 of 5	NP_001333719.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSR2	ENST00000375151.5	TSL:1 MANE Select	c.167G>T	p.Arg56Leu	missense	Exon 2 of 5	ENSP00000364293.4	Q969E8
	TSR2	ENST00000908048.1		c.167G>T	p.Arg56Leu	missense	Exon 2 of 5	ENSP00000578107.1
	TSR2	ENST00000960847.1		c.167G>T	p.Arg56Leu	missense	Exon 2 of 5	ENSP00000630906.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000643 AC: 1 AN: 155634 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000465 AC: 5 AN: 1075545 Hom.: 0 Cov.: 29 AF XY: 0.00000290 AC XY: 1 AN XY: 344679

African (AFR) AF: 0.00 AC: 0 AN: 25841

American (AMR) AF: 0.00 AC: 0 AN: 33063

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18065

East Asian (EAS) AF: 0.00 AC: 0 AN: 29407

South Asian (SAS) AF: 0.00 AC: 0 AN: 50658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39801

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4001

European-Non Finnish (NFE) AF: 0.00000603 AC: 5 AN: 829608

Other (OTH) AF: 0.00 AC: 0 AN: 45101

GnomAD4 genome Cov.: 23

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.22
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.030
Sift	Benign	0.32	T
Sift4G	Benign	0.19	T
Polyphen		0.21	B
Vest4		0.21
MVP		0.10
MPC		0.68
ClinPred		0.44	T
GERP RS		2.4
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.36
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140822042; hg19: chrX-54467208;